The invention derives from the need to solve at least two related problems within the pharmaceutical industry: (1) inaccurate or inconsistent dose division upon breaking of a dosage form, and (2) inflexibility in adjusting the dose of only one active ingredient in a combination dosage form.
With regard to the first problem of inconsistent or inaccurate dose division, it is known that pharmaceutical tablets are commonly broken to modify the dose provided by a whole tablet. These dosage adjustments through tablet breaking by patients have been determined to be imprecise. Scoring of pharmaceutical tablets is well known. Scoring of pharmaceutical tablets produced in a layered fashion is also known but has been employed less extensively. Scores into a tablet have not exceeded 1 mm in depth. Tablets are often produced with a score to aid breaking, but such tablet breaking is well-documented to suffer many problems whether or not scoring of the tablet is provided. Even though inaccurate breaking of scored tablets is a well-known problem, attention has not been paid to solving this problem by creating segmented (e.g., layered) tablets in a tablet press with a segment that provides some or most of said breaking region when the tablet is broken, and pari passu provides physical, support for the part of the tablet with the deep score. Many drugs, such as warfarin, require dosage adjustments during treatment and the scored tablets of the marketed warfarin products are frequently broken to achieve this dosage adjustment. These dosage adjustments through tablet breaking by patients have been determined to be imprecise.
Experts for many years have called upon the pharmaceutical industry to improve the quality of tablet breaking, yet such has not been optimized until the current invention. In 1984, Stimpel et al. (“Stimpel”), described the relative accuracy of breaking various tablets for treatment of cardiovascular problems. M. Stimpel et al., “Breaking Tablets in Half,” The Lancet (1964):1299. Even though breaking was performed by a sophisticated, dexterous person, Stimpel found that breaking was not accurate, and opined that real world use by patients would provide even more unsatisfactory results.
Rodenhuis et al., (2004) observed that European regulatory authorities, in 1998, started a policy to discourage scoring of tablets. This policy change, according to Rodenhuis, likely related to “many recent reports of bad functioning score lines,” that “many scored tablets are difficult to break,” and that “many scored tablets show unsatisfactory mass uniformity of the subdivided halves.” Rodenhuis reported that 31% of all tablets in one Netherlands study were subdivided before being swallowed. Rodenhuis noted that “[i]mproving the functioning of score lines may be a more practical approach than banning this [scored] dosage form”. N. Rodenhuis et al., “The rationale of scored tablets as dosage form.” European J. of Pharmaceutical Sciences 21 (2004):305-308. See also, van Santen, E., Barends, D. M. and Frijlink, H. W. “Breaking of scored tablets: a review.” European J. of Pharmaceutics and Biopharmaceutics 53 (2002):139-145 for a comprehensive review article on this topic.
Peek et al., (2002), studied tablet splitting by “elderly patients” aged 50-79. Peek, B. T., Al-Achi, A., Coombs, S. J. “Accuracy of Tablet Splitting by Elderly Patients.” The Journal of the American Medical Association 288 No. 4 (2002):139-145. Breaking scored tablets with mechanical tablet splitters without specific instruction led to highly unsatisfactory separating of the tablets. For example, warfarin 5 mg was on average split into 1.9 and 3.1 mg tablets. This potent anticoagulant has such a narrow therapeutic range that 2, 2.5, and 3 mg tablet doses are manufactured. Biron et al., (1999), demonstrated that warfarin 10 mg also often split, to less than 4.25 or greater than 5.75 mg. Biron, C., Liczner, P., Hansel, S., Schved, J. F., “Oral Anticoagulant Drugs Do Not Cut Tablets in Quarters.” Throittb Haemost 1201 (1999). In addition, they demonstrated that loss of mass due to crumbling or chipping of the breaking of the warfarin tablets was statistically significant. They also demonstrated that quartering of the tablets was grossly inaccurate.
McDevitt et al., (1998), found that 25 mg unscored hydrochlorothiazide (HCTZ) tablets were manually split badly enough that 12.4% deviated by more than 20% from ideal weight. McDevitt, J. T., Gurst, A. H., Chen, Y. “Accuracy of Tablet Splitting.” Pharmacotherapy 18 No. 1 (1998):193-197. 77% of the test subjects stated they would be willing to pay a premium for individually produced HCTZ 12.5 mg tablets rather than split unscored 25 mg tablets.
Rosenberg et al., studied pharmacist-dispensed split tablets. Rosenberg, J. M., Nathan, J. P., Plakogiannis, F. “Weight Variability of Pharmacist-Dispensed Split Tablets,” Journal of American Pharmaceutical Association 42 No. 2 (2002):200-205. They found that “tablet splitting resulted in an unacceptably high incidence of weight variation” and recommended that “standards should be developed to ensure uniformity of split tablets.”
Teng et al., (2002), using a trained individual in a laboratory setting to split tablets, concluded that “the majority of the 11 drug products we tested, when assessed for their: ability to be split into half-tablets of equal dose, failed a liberally interpreted USP (United States Pharmacopoeia) uniformity test . . . . The practice of dividing tablets to save costs or to improve a dosage regimen . . . is not recommended for patients using drugs with more substantial toxicity and steep dose-response efficacy curves.” Teng, J., Song, C. K., Williams, R. L., Polli, J. E. “Lack of Medication Dose Uniformity in Commonly Split Tablets.” Journal of American Pharmaceutical Association 42 No. 2 (2002):195-199.
In the U.S., many “managed care” insurance organizations recommend or encourage patients to split or divide tablets, including unscored or irregularly-shaped tablets. Many drug products in the US are unscored or are provided as capsules despite being able to be formed as tablets. The dosage forms and methods of the subject invention can advantageously provide a patient with the capability to comply with such recommendations by the managed care insurance organizations
A second problem arising from dividing or breaking a dosage form relates to combination drug products, i.e., single or unitary dosage forms containing two or more active ingredients. Combination dosage forms are typically produced as homogeneous mixtures or as capsules. A physician prescribing these combination products, such as a combination product currently available to treat arterial hypertension, may not adjust the dose of only one active ingredient in the combination product without a consequent proportional adjustment to the dose of the other active ingredient(s).
Combination dosage forms can thus be disadvantageous due to the inflexibility of dealing with changing circumstances such as fluctuating blood pressure or the appearance of side effects to a drug. An adjustment to the dose of one of the active ingredients in a commonly available combination product necessarily results in the dose adjustment of the other active ingredient or ingredients contained in that same dosage form. Clearly, dividing a tablet or capsule containing a homogeneous mixture of two or more active ingredients divides each of the active ingredients in that homogeneous mixture. Even if the actives are layered separately, the layer configuration of currently available combination dosage forms is such that breaking of the tablet results in breaking through all layers, thus dividing all active ingredients proportionally. This disadvantage has been propounded many times over the years, and has hindered the acceptability of certain combination products, for example, in treatments for arterial hypertension (“hypertension”). Nevertheless, even with these disadvantages, combination treatments for hypertension have proven popular for cost and potential compliance reasons. Accordingly, there is a need for combination products which can provide the flexibility of adjusting the dose of one of the actives without necessarily adjusting the dose of the other active(s) contained within the combination dosage form.
There is no controlled release dosage form provided in the prior art that fully addresses these problems facing the industry. The prior art does not describe a dosage form having two layers of active drug or drugs, at least one of which is a controlled release layer, in different places within a tablet with an interposed different layer that can be broken through by application of manual pressure to accurately and consistently provide modified or divided doses of the active drug or drugs.
Certain combination drug products have been described or marketed having the two or more active ingredients provided in different layers. For example, U.S. Pat. No. 5,738,874 to Conte, et al. describes a multi-layer controlled release tablet having a first layer comprising an immediate release drug composition, a second layer comprising a slow release drug composition, and a third layer comprising a barrier composition to modify release of drug from the layer adjacent thereto. This third, drug-free layer is not interposed between the drug-containing layers and is not useful for facilitating breakage or splitting of the tablet.
Published U.S. Application 2005/0019407A1 describes a composite dosage form which has first and second portions joined at an interface. These dosage forms have a first molded material and a second compressed material. There is no disclosure of any modification of the disclosed dosage forms that would facilitate the breaking of the dosage forms into any subdivided form.
U.S. Pat. No. 6,602,521 describes a multiplex drug delivery system containing at least two immediate release drug dosage packages enveloped by a scored, extended release compartment. There is no teaching from the disclosure of this patent of a controlled release compartment which does not envelop the immediate release compartments.
Combination products having at least two layers comprising active drug, separated by an interposed inactive layer (i.e., one derived from a granulation lacking drug) are known. However, these prior art dosage forms are provided only when there is a physical or chemical incompatibility between the different layers containing active drug. In that case of incompatible active layers, the prior art specifically teaches that said “separating layer” be of as limited a size as is necessary to separate the incompatible layers.
Commercially, the only pharmaceutical product to our knowledge that is produced as a taller-than-wide dosage form is Concerta®, which is a layered tablet, having a semi-permeable membrane and utilizes the ORGS® system for its controlled release characteristics. The manufacturer's directions for the use of Concerta® specify that the tablets should never be broken. Concerta® does not include a score and does not include an inactive layer interposed between, and therefore separating, active controlled release layers. Except for Concerta®, tablets have not been produced that are wider than they are tall, including those involving layers vertically disposed one on the other.
The present invention, as disclosed herein, can overcome or alleviate both of the problems discussed above, and can provide additional advantages and address additional problems as would be well understood and recognised in the art.